A unique schedule of palonosetron, ondansetron, and dexamethasone for the prevention of delayed nausea and vomiting in patients receiving myeloablative chemotherapy.

Myeloablative chemotherapy administered prior to autologous stem cell transplantation (auto-SCT) is associated with a significant amount of chemotherapy-induced nausea and vomiting (CINV). We conducted a phase II trial to assess the safety, efficacy, and impact on quality of life when palonosetron (PAL) 0.25 mg combined with dexamethasone were given on the final or only day of myeloablative chemotherapy for auto-SCT. The primary end point of this study was the incidence of achieving a delayed CINV complete response defined as no emetic episode and no use of rescue medications during the 24-120 h period post chemotherapy. Eighty-five patients were enrolled in the study and received PAL. A delayed CINV complete response was achieved in 15% of patients. A multivariate analysis demonstrated no associated differences between age, gender, diagnosis, or regimen. By day 5 after PAL, the mean nausea severity was 0.91 ± 2.45 vs. 0.09 ± 1.58 at baseline (p = 0.012). Quality of life measurements demonstrated similar quality of life between baseline and day 3. By day 6 however, nausea alone had a statistically significant impact on quality of life. In our study, PAL controlled nausea severity and sustained quality of life, but further strategies are needed to control delayed CINV associated with the auto-SCT process.

Allogeneic hematopoietic cell transplantation for metastatic breast cancer.

We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3-64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03). A total of 9 of 33 patients (27%) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a graft-vs-tumor (GVT) effect. Progression-free survival (PFS) at 1 year was 23% with myeloablative conditioning and 8% with RIC (P=0.09). Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: P=0.03), consistent with a GVT effect, but this did not affect PFS. These findings support the need for preclinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.

Post-relapse survival after haploidentical transplantation vs matched-related or matched-unrelated hematopoietic cell transplantation.

Relapse remains a major cause of mortality among patients receiving allogeneic hematopoietic cell transplantation (HCT). The impact of donor type on post-relapse survival (PRS) has not been widely examined. We compared the survival outcomes for patients relapsing after haploidentical donor transplantation (HIDT) using post-transplant cyclophosphamide with those relapsing after matched-related donor transplantation (MRDT) or matched-unrelated donor transplantation (MUDT) at our institution. Two hundred and thirty-seven consecutive HCT recipients with relapse occurring after HIDT (N=48), MUDT (N=87) and MRDT (N=102) were included in this analysis. Median age was 49 years (19-77 years) and the median time to relapse was 156 days (12-2465) after HCT. HIDT recipients had similar median time to relapse (5.8 vs 4.8 vs 5.5 months, P=0.638) compared with MUDT and MRDT, respectively. One-year PRS was worse among HIDT recipients compared with MRDT and MUDT (17% vs 46% vs 40%, P<0.05). In a multivariate analysis, time to relapse (<3 vs >3 months post transplant), no use of donor lymphocyte infusion (DLI) following relapse, higher Dana Farber disease risk index and HCT comorbidity index scores at the time of transplant and delayed platelet engraftment post transplant were all predictive of worse PRS. This analysis shows that 1-year PRS is inferior among HIDT when compared with MRDT or MUDT. Lower use of DLI after HIDT may have contributed to this inferior survival.

Preferential depletion of host over donor T cells through in vivo decay of active rabbit-anti-thymocyte globulin levels during reduced intensity conditioning.

Inadequate T-cell chimerism following reduced-intensity conditioning transplantation may contribute to graft rejection and disease relapse. Anti-thymocyte globulin (ATG) enhances early donor T-cell chimerism, but may also deplete donor T cells, increasing risks of infection and relapse. We prospectively tested administration of rabbit ATG (rATG) ⩾14 days before the infusion of the graft, followed by in vivo decay of active rATG levels, to selectively deplete host T cells. Twenty-three patients received rATG total dose 4.5 mg/kg on days -16 and -15, fludarabine 30 mg/m(2) per day on day -7 through -3, IV busulfan 130 mg/m(2) per day on days -4 and -3 and cyclophosphamide 1500 mg/m(2) on day -2. rATG levels were therapeutic in all patients on day -14, but were sub-therapeutic (<1 µg/mL) by day 0 in 82% of patients. Median donor T-cell chimerisms on days 30 and 180 were 100% (75-100%) and 100% (90-100%), respectively. Non-relapse mortality and relapse/progression at 48 months were 17 and 30%. Cumulative incidences of acute GvHD grades II-IV and III-IV were 39 and 9%. Median follow-up is 64 months (46-79 months). Survival and disease-free survival at 48 months were 70 and 52%. These data suggest that selective depletion of host T cells using this regimen is a feasible and effective strategy.

High-dose CEB vs BEAM with autologous stem cell transplant in lymphoma.

Between January 1996 and July 2002, 72 patients with non-Hodgkin's lymphoma or Hodgkin's disease underwent high-dose chemotherapy with autologous stem cell transplant conditioned with either cyclophosphamide, etoposide, carmustine (CEB) or carmustine, etoposide, cytarabine, melphalan (BEAM) at a single institution. In all, 52 patients received CEB and 20 patients received the BEAM regimen. Patient characteristics that were significantly different between the two groups are tumor grade and extranodal involvement (P = 0.0196, 0.0341, respectively). Regimen-related toxicities examined yielded only diarrhea occurring at a higher rate in the BEAM group (81 vs 51%, P = 0.0026), although cases were milder (92 vs 57%). Patients treated with CEB developed mucositis at a slightly higher rate (79%) than patients treated with BEAM (75%), but this difference did not reach statistical significance. However, the mucositis that occurred within the BEAM group was predominately mild (67%) in contrast to the predominance of moderate to severe cases in the CEB group (74%). In addition, patients treated with CEB required growth factor support for a longer time than patients treated with BEAM (P = 0.0399). Response rates were high in both groups, with trends favoring the BEAM group. Overall survival was higher after treatment with BEAM than with CEB (84 vs 60%).

FLAG chemotherapy followed by allogeneic stem cell transplant using nonmyeloablative conditioning induces regression of myelofibrosis with myeloid metaplasia.

A 38-year-old woman with agnogenic myeloid metaplasia complicated by the poor prognostic factors of severe osteosclerosis, prominent hepatosplenomegaly, and profound anemia was treated with FLAG chemotherapy to decrease her organomegaly before undergoing a nonmyeloablative allogeneic stem cell transplant from a matched-sibling donor. The patient's pre- and post transplant course were complicated by an autoimmune disorder and her post transplant course was complicated by severe hepatic and gastrointestinal GVHD. A technetium-99m sulfur colloid scan 4 months post transplant and bone marrow studies 8 months post transplant demonstrated intramedullary hematopoiesis, complete resolution of marrow fibrosis, and partial resolution of osteosclerosis.

Beneficial effect of intravenous lidocaine in cutaneous chronic graft-versus-host disease secondary to donor lymphocyte infusion.

We report two cases of refractory chronic graft-versus-host disease after donor lymphocyte infusions in which the skin lesions improved dramatically with the use of intravenous pulses of lidocaine. This form of therapy has been used successfully for the cutaneous involvement of scleroderma and may have vasodilator and anti-inflammatory effects.

A phase II study of two cycles of high-dose chemotherapy with autologous stem cell support in patients with metastatic breast cancer who meet eligibility criteria for a single cycle.

Multi-cycle high-dose chemotherapy with autologous stem cell support (HDC-ASCS) may improve the results obtained with single-cycle HDC-ASCS in metastatic breast cancer (MBC). However, the tolerability and efficacy of additional cycles of HDC-ASCS in patients selected using standard eligibility criteria for single cycle HDC-ASCS is uncertain. Twenty-nine patients with MBC and a CR or PR to induction chemotherapy were selected by standard institutional eligibility criteria for single-cycle HDC-ASCS. Cycle 1 HDC-ASCS (cyclophosphamide 6 g/m2; mitoxantrone 70 mg/m2; carboplatin 800 mg/m2) was followed by a planned second cycle (etoposide 1.6 g/m2; thiotepa 800 mg/m2; carboplatin 800 mg/m2 modulated by tamoxifen 120 mg/m2/day x 5 days) with a median interval of 3.2 months. CR rate was 20% after induction chemotherapy and 33% and 54% after HDC cycles I and II, respectively. Sixteen patients (55%) failed to complete HDC cycle II within 200 days because of disease progression, toxicity, inadequate stem cell collection, insurance denials or patient choice. Median progression-free survival (PFS) for all 29 patients entered is 301 days from date of HDC cycle I and actuarial PFS at 2 years is 35%. For the 13 patients who received the two cycles of HDC-ASCS, actuarial PFS at 2 years was 54% (P = NS compared to those receiving only one cycle). These data show that a second cycle of full-dose intensity HDC-ASCS may increase the proportion of patients with MBC that achieve CR and may increase PFS. However, a large proportion of patients that complete HDC-ASCS cycle I may fail to proceed to cycle II in a timely fashion. Bone Marrow Transplantation (2000) 25, 519-524.

Autotransplants for Hodgkin's disease in first relapse or second remission: a report from the autologous blood and marrow transplant registry (ABMTR).

Although patients with relapsed Hodgkin's disease have a poor prognosis with conventional therapies, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autotransplantation) may provide long-term progression-free survival. We reviewed data from the Autologous Blood and Marrow Transplant Registry (ABMTR) to determine relapse, disease-free survival, overall survival, and prognostic factors in this group of patients. Detailed records from the ABMTR on 414 patients with Hodgkin's disease in first relapse (n = 295) or second complete remission (CR) (n = 119) receiving an autotransplant from 1989 to 1995 were reviewed. Median age was 29 (range, 7-64) years. Median time from diagnosis to relapse was 18 (range, 6-219) months; median time from relapse to transplant was 5 (range, <1-215) months. Most patients received high-dose chemotherapy without total body irradiation for conditioning (n = 370). The most frequently used high-dose regimen was cyclophosphamide, BCNU, VP-16 (CBV) (n = 240). The graft consisted of bone marrow (n = 246), blood stem cells (n = 112), or both (n = 56). Median follow-up was 46 (range, 5-96) months. One hundred-day mortality (95% confidence interval) was 7 (5-9)%. One hundred and sixty-five of 295 patients (56%) transplanted in relapse achieved CR after autotransplantation. Of these, 61 (37%) recurred. Twenty-four of 119 patients (20%) transplanted in CR recurred. The probability of disease-free survival at 3 years was 46 (40-52)% for transplants in first relapse and 64 (53-72)% for those in second remission (P < 0.001). Overall survival at 3 years was 58 (52-64)% after transplantation in first relapse and 75 (66-83)% after transplantation in second CR (P < 0.001). In multivariate analysis, Karnofsky performance score <90% at transplant, abnormal serum LDH at transplant, and chemotherapy resistance were adverse prognostic factors for outcome. Progression of Hodgkin's disease accounted for 69% of all deaths. Autotransplantation should be considered for patients with Hodgkin's disease in first relapse or second remission. Future investigations should focus on strategies designed to decrease relapse after autotransplantation, particularly in patients at high risk for relapse.

Induction of molecular remission by donor peripheral blood leukocyte therapy in patients relapsing with extramedullary blastic phase chronic myeloid leukemia after allogeneic bone marrow transplantation.

Two patients with chronic myeloid leukemia (CML) who relapsed in blastic transformation after allogeneic bone marrow transplantation (BMT) were treated with infusions of leukapheresed peripheral blood mononuclear cells from their original donor. At relapse, their disease was characterized by symptomatic extramedullary deposits of leukemia with minimal (PCR positive, cytologically negative) involvement of bone marrow. Treatment with donor cell infusions was associated with clinical remission, return of full donor chimerism and loss of the BCR-ABL transcript detectable in bone marrow before donor leukocyte infusion (molecular remission). Donor leukocyte infusions should be considered for therapy of relapsed blastic phase CML after allogeneic BMT, especially when the relapse is primarily extramedullary and responsive to local and systemic cytoreductive therapy. However, severe GVHD and CNS relapse remain obstacles to achieving a successful long-term outcome.

Use of capecitabine as first-line therapy in patients with metastatic breast cancer relapsing after high-dose chemotherapy and autologous stem cell support.

High-dose chemotherapy with autologous stem cell support (HDC-ASCS) can produce high complete remission rates in patients with metastatic breast cancer (MBC). However, the majority of those so treated will relapse within 3 years. The ability of such patients to tolerate further myelosuppressive chemotherapy may be limited and the best therapy is undefined. In this retrospective study we assessed the role of capecitabine as initial therapy after relapse. Ten patients (median age = 47 years; oestrogen receptor-positive, n = 4; visceral disease, n = 6; prior anthracycline, n = 8, prior taxanes, n = 10), whose disease progressed at a median of 246 days (range 69-480) after HDC-ASCS and who were treated with capecitabine (2500 mg/m2 per day for 2 weeks of a 3-week cycle) as initial therapy for relapse, were assessed retrospectively for response and toxicity. They received a median of eight cycles (range 4-24) of capecitabine. The toxicities encountered while receiving capecitabine were: hand-foot syndrome (grade 1, n = 3; grade 2, n = 4; grade 3, n = 1); diarrhoea (grade 1, n = 1; grade 2, n = 3); nausea (n = 2) and fatigue (n = 5). Haematological toxicity was seen in only one patient. No patient required hospitalization for toxicity. Three achieved a complete remission, four a partial remission and three disease stabilization. After a median follow-up of 183 days from commencing capecitabine (range 97-540), all patients were alive and five were in remission. Five progressed after remissions that lasted between 63 and 252 days. Oral capecitabine is an active and well-tolerated agent when used alone as first-line therapy in patients who have relapsed after HDC-ASCS for MBC.

T-cell replete haploidentical donor transplantation using post-transplant CY: an emerging standard-of-care option for patients who lack an HLA-identical sibling donor.

Availability of an HLA-identical sibling (MRD) or suitably matched unrelated donor (MUD) has historically been a limiting factor in the application of allogeneic hematopoietic transplantation. Although almost all patients have an HLA-haploidentical family donor, prior attempts at transplantation from such donors using T-cell replete grafts and conventional immunosuppression were associated with unacceptable rates of GVHD, and when stringent ex vivo T-cell depletion was used to control GVHD, rates of graft rejection and post-transplant infections were prohibitive. The recent approach to HLA-haploidentical donor transplantation developed in Baltimore that uses T-cell replete grafts and post-transplant CY (Haplo-post-HCT-CY) to control post-transplant allo-reactivity appears to have overcome many of the obstacles historically associated with haploidentical donor transplantation. In particular, TRM rates of <10% are usual and rapid reconstitution of immunity leads to a low rate of post-transplant infections and no post-tranplant lymphoproliferative disorders (PTLD), consistent with the hypothesis that post-transplant CY selectively depletes proliferating alloreactive T cells responsible for GVHD and graft rejection while preserving resting memory T cells essential for post-transplant immunologic recovery. In parallel trials using similar non-myeloablative conditioning regimens, Haplo-post-HCT-CY produced similar overall survival to double umbilical cord blood transplantation(DUCBT) in adult patients (62% vs 54%), with low rates of TRM (7% vs 24%), severe acute GVHD (0% vs 21%) and chronic GVHD (13% vs 25%). Furthermore, recent non-randomized comparisons adjusted for risk factors show that Haplo-post-HCT-CY achieve at least equivalent outcomes to conventional MRD and MUD transplants. Although most experience has been obtained using BM, emerging data suggest that a G-CSF mobilized PBSC graft can also safely be used for Haplo-post-HCT-CY. Haplo-post-HCT-CY also avoids the graft acquisition costs of DUCBT and MUDs and the cost of cell selection associated with T-depleted grafts. Although randomized comparisons will be forthcoming, Haplo-post-HCT-CY can already be considered a valid standard-of-care in patients who lack conventional donors thus extending the availability of allogeneic transplants to almost all patients. This donor source may also challenge the routine preference for a MUD in patients lacking an MRD.

Preemptive DLI without withdrawal of immunosuppression to promote complete donor T-cell chimerism results in favorable outcomes for high-risk older recipients of alemtuzumab-containing reduced-intensity unrelated donor allogeneic transplant: a prospective phase II trial.

Although pretransplant alemtuzumab can reduce GVHD following allogeneic transplantation, it may also increase the risk of mixed donor T-cell chimerism and infections. We hypothesized that the early use of DLI without withdrawal of immunosuppressive drugs in patients with mixed T-cell chimerism would lower the risk of relapse without significantly increasing the risk of GVHD post DLI. Thirty-six patients (median age 59 years) were treated in this phase II trial using reduced-intensity conditioning including s.c. alemtuzumab (total dose 43 mg) and a PBSC graft from a matched unrelated donor (UD). DLI without withdrawal of immunosuppressive drugs was administered to all 25 patients with <50% donor T-cell chimerism on day +60. The cumulative risks of acute and chronic GVHD were 42% and 59%, respectively. Estimated probabilities of non-relapse mortality (NRM) at day 100 and 1 year were 3% and 14%, respectively. With a median follow up 2.4 years, estimated survivals at day 100, 1 and 2 years were 97%, 71% and 57%, respectively. In multivariate analysis, the occurrence of acute GVHD was associated with an increased risk of mortality, whereas the occurrence of chronic GVHD had a protective effect, associated with decreased relapse and improved disease-free survival. Low-dose alemtuzumab and preemptive DLI provides favorable transplant outcomes including low NRM in an older patient population with high-risk malignancies undergoing UD transplantation.

Outpatient myeloablative allo-SCT: a comprehensive approach yields decreased hospital utilization and low TRM.

Historically, myeloablative allogeneic hematopoietic SCT (HSCT) has required prolonged in-patient hospitalization due to the effects of mucosal toxicity and prolonged cytopenias. We explored the safety and feasibility of outpatient management of these patients. A total of 100 consecutive patients underwent a matched-related donor myeloablative allogeneic HSCT for a hematologic malignancy at a single institution. Patients were hospitalized briefly for stem-cell infusion and thereafter only for complications more safely managed in the in-patient setting. The median hospital length of stay from the start of the preparative regimen to day +30 and day +100 post-transplant was 12 and 15 days, respectively. Planned hospital discharge occurred in 79 patients after stem cell infusion. Patients were readmitted to hospital at median of day +7 post transplant, with neutropenic fever being the primary cause for readmission. In total, 18 patients required no in-patient care in the first 100 days. Non-relapse mortality at day 100 and 6 months was 10 and 15%, respectively, for all patients, and 0 and 5%, respectively, for standard risk patients. In summary, outpatient myeloablative allogeneic HSCT with expectant in-patient management can be accomplished safely with low treatment-related morbidity and mortality. Clinical outcomes seem comparable to those reported for traditional in-patient management.

Is the International Staging System superior to the Durie-Salmon staging system? A comparison in multiple myeloma patients undergoing autologous transplant.

The international staging system (ISS) for multiple myeloma (MM) is a validated alternative to the Durie-Salmon staging system (DSS) for predicting survival at diagnosis. We compared these staging systems for predicting outcomes after upfront autologous stem cell transplantation by analyzing the outcomes of 729 patients between 1995 and 2002. With a median follow-up of 56 months, the univariate probabilities (95% CI) of non-relapse mortality (NRM), relapse, progression-free survival (PFS) and overall survival (OS) at 5 years were 7, 68, 25 and 52%, respectively. The median OS for stages I, II, III by DSS and ISS were 82, 68, 50 and 64, 68, 45 months, respectively. The concordance between the two staging systems was only 36%. Staging systems were formally compared using Cox models fit with DSS and ISS stages. The relative risks of PFS and OS were significantly different for stages I vs II and II vs III for DSS, but only for stages II vs III for ISS. Although both systems were predictive of PFS and OS, the DSS was superior in formal statistical comparison using Brier score. However, neither system was strongly predictive of outcomes, indicating the need for newer schemes incorporating other prognostic markers.

Sequential acquisition of trisomy 8 and N-ras mutation in acute myeloid leukaemia demonstrated by analysis of isolated leukaemic colonies.

Specific chromosomal aberrations and point mutations of the N-ras proto-oncogene are characteristic genetic alterations in acute leukaemias. However, the relationships between these two different genetic changes are unclear. Here we have determined the order of genetic events in a patient with acute myeloid leukaemia characterized by trisomy 8 and a point mutation of N-ras at codon 12 (N12-cys) and codon 61 (N61-his). 30 colonies obtained by in vitro clonogenic assay of leukaemic cells from a patient with AML were individually analysed for the presence of trisomy 8 and each of two different N-ras mutations by fluorescence in situ hybridization (FISH) and the polymerase chain reaction (PCR). Trisomy 8 was detected in 25/26 evaluable colonies. 19/26 colonies contained the N12-cys mutation. The N61-his mutation was not detected in any of the colonies obtained. All the colonies with the N12 cys mutation were also trisomic from chromosome 8, whereas 6/25 colonies with trisomy 8 had no N-ras mutation. These data suggest that trisomy 8 was acquired before N12 cys mutation in the pathogenesis of this leukaemia and that two genetic events can co-operate within a single subclone.

Proliferative but not nonproliferative responses to granulocyte colony-stimulating factor are associated with rapid activation of the p21ras/MAP kinase signalling pathway.

Granulocyte colony-stimulating factor (G-CSF) can elicit responses that include proliferation, granulocytic differentiation, and activation of cellular functions in target cells. The biochemical pathways responsible for transduction of these signals from the G-CSF receptor (G-CSFR) have not been defined. In this report, we show that, in murine (NFS-60) and human (OCI-AML 1) myeloid leukemia cell lines and in murine pro-B-lymphocytic cells, BAF/B03, transfected with the murine G-CSFR, proliferative responses to G-CSF are associated with rapid activation of p42 and p44 MAP kinases and p21ras. Truncation of the cytoplasmic portion of the murine G-CSFR at residue 646 but not at residue 739 abolished G-CSF-induced stimulation of cellular proliferation as well as activation of MAP kinase and p21ras in transfected BAF/B03 cells. G-CSF-induced granulocytic differentiation of the murine leukemic cell line 32DC13(G) occurred in the absence of detectable activation of p42 MAP kinase. Nonproliferative responses to G-CSF in the human promyelocytic cell line HL-60 and in human neutrophils were similarly associated with no MAP kinase activation. These results imply that differing cellular effects of G-CSF may be involve the recruitment of differing signal transduction pathways with the p21ras/MAP kinase pathway being limited to proliferative responses.

Non-lymphoid blast crisis of CML with rearrangement of immunoglobulin and T-cell receptor delta genes.

We report a patient with chronic myeloid leukaemia (Philadelphia-positive with M-BCR rearrangement) in transformation whose blast cells had myelomonocytic morphology, absent terminal deoxynucleotidyl transferase expression and non-lymphoid cell surface markers (CD10-, CD19-, CD33+, CD14+, CD11+). Leukaemia cell DNA showed rearrangement of both immunoglobulin heavy chain and T-cell receptor delta genes. Such rearrangements may be a feature of a small proportion of patients with non-lymphoid transformation of CML as they are in a minority of cases of de novo acute non-lymphoblastic leukaemia.